4do5: Difference between revisions
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==Pharmacological chaperones for human alpha-N-acetylgalactosaminidase== | ==Pharmacological chaperones for human alpha-N-acetylgalactosaminidase== | ||
<StructureSection load='4do5' size='340' side='right' caption='[[4do5]], [[Resolution|resolution]] 1.51Å' scene=''> | <StructureSection load='4do5' size='340' side='right' caption='[[4do5]], [[Resolution|resolution]] 1.51Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[4do5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/ | <table><tr><td colspan='2'>[[4do5]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DO5 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DO5 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DGJ:(2R,3S,4R,5S)-2-(HYDROXYMETHYL)PIPERIDINE-3,4,5-TRIOL'>DGJ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=BMA:BETA-D-MANNOSE'>BMA</scene>, <scene name='pdbligand=CIT:CITRIC+ACID'>CIT</scene>, <scene name='pdbligand=DGJ:(2R,3S,4R,5S)-2-(HYDROXYMETHYL)PIPERIDINE-3,4,5-TRIOL'>DGJ</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=NAG:N-ACETYL-D-GLUCOSAMINE'>NAG</scene>, <scene name='pdbligand=MAN:ALPHA-D-MANNOSE'>MAN</scene></td></tr> | ||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3h53|3h53]], [[3h54|3h54]], [[3h55|3h55]], [[3igu|3igu]], [[4do4|4do4]], [[4do6|4do6]]</td></tr> | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3h53|3h53]], [[3h54|3h54]], [[3h55|3h55]], [[3igu|3igu]], [[4do4|4do4]], [[4do6|4do6]]</td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NAGA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">NAGA ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | ||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Alpha-N-acetylgalactosaminidase Alpha-N-acetylgalactosaminidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.49 3.2.1.49] </span></td></tr> | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Alpha-N-acetylgalactosaminidase Alpha-N-acetylgalactosaminidase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.2.1.49 3.2.1.49] </span></td></tr> | ||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4do5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4do5 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4do5 RCSB], [http://www.ebi.ac.uk/pdbsum/4do5 PDBsum]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4do5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4do5 OCA], [http://pdbe.org/4do5 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4do5 RCSB], [http://www.ebi.ac.uk/pdbsum/4do5 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4do5 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | </div> | ||
<div class="pdbe-citations 4do5" style="background-color:#fffaf0;"></div> | |||
== References == | == References == | ||
<references/> | <references/> | ||
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</StructureSection> | </StructureSection> | ||
[[Category: Alpha-N-acetylgalactosaminidase]] | [[Category: Alpha-N-acetylgalactosaminidase]] | ||
[[Category: | [[Category: Human]] | ||
[[Category: Clark, N E]] | [[Category: Clark, N E]] | ||
[[Category: Garman, S C]] | [[Category: Garman, S C]] | ||
Revision as of 12:57, 4 August 2016
Pharmacological chaperones for human alpha-N-acetylgalactosaminidasePharmacological chaperones for human alpha-N-acetylgalactosaminidase
Structural highlights
Disease[NAGAB_HUMAN] Defects in NAGA are the cause of Schindler disease (SCHIND) [MIM:609241]. Schindler disease is a form of NAGA deficiency characterized by early onset neuroaxonal dystrophy and neurological signs (convulsion during fever, epilepsy, psychomotor retardation and hypotonia). NAGA deficiency is typically classified in three main phenotypes: NAGA deficiency type I (Schindler disease or Schindler disease type I) with severe manifestations; NAGA deficiency type II (Kanzazi disease or Schindler disease type II) which is mild; NAGA deficiency type III (Schindler disease type III) characterized by mild-to-moderate neurologic manifestations. NAGA deficiency results in the increased urinary excretion of glycopeptides and oligosaccharides containing alpha-N-acetylgalactosaminyl moieties. Inheritance is autosomal recessive.[1] [2] Defects in NAGA are the cause of Kanzaki disease (KANZD) [MIM:609242]; also known as NAGA deficiency type II or Schindler disease type II. Kanzaki disease is an autosomal recessive disorder characterized by late onset, angiokeratoma corporis diffusum and mild intellectual impairment.[3] [4] Function[NAGAB_HUMAN] Removes terminal alpha-N-acetylgalactosamine residues from glycolipids and glycopeptides. Required for the breakdown of glycolipids.[5] Publication Abstract from PubMedSchindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal alpha-N-acetylgalactosaminidase (alpha-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human alpha-NAGAL both in vitro and in vivo. We demonstrate that a related iminosugar DGJ (currently in phase III clinical trials for another metabolic disorder, Fabry disease) can also chaperone human alpha-NAGAL in Schindler/Kanzaki disease. The 1.4- and 1.5-A crystal structures of human alpha-NAGAL complexes reveal the different binding modes of iminosugars compared with glycosides. We show how differences in two functional groups result in >9 kcal/mol of additional binding energy and explain the molecular interactions responsible for the unexpectedly high affinity of the pharmacological chaperones. These results open two avenues for treatment of Schindler/Kanzaki disease and elucidate the atomic basis for pharmacological chaperoning in the entire family of lysosomal storage diseases. Pharmacological chaperones for human alpha-N-acetylgalactosaminidase.,Clark NE, Metcalf MC, Best D, Fleet GW, Garman SC Proc Natl Acad Sci U S A. 2012 Oct 23;109(43):17400-5. doi:, 10.1073/pnas.1203924109. Epub 2012 Oct 8. PMID:23045655[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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